DE60309465T2 - A method of inhibiting or preventing urogenital atrophy and its symptoms in women - Google Patents

Abstract

This invention relates to a method for inhibition of skin atrophy, or epithelial or mucosal atrophy in women, or to a method for treatment or prevention of symptoms related to atrophy, said method comprising administering to the woman an effective amount of the compound of formula (I) or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt, an ester thereof or a metabolite thereof.

Description

FIELD OF THE INVENTION

These This invention relates to a method of inhibiting urogenital Atrophy in women, especially women during or after menopause. The invention also relates to the prevention or treatment of urogenital Atrophy-related symptoms in women, especially women during or after the menopause.

BACKGROUND OF THE INVENTION

While and After menopause, elderly women often develop symptoms related to estrogen deficiency are attributed. Close these symptoms Hot flashes, sweating, Asomnia, depression, vaginal dryness, urinary incontinence, nausea, Pain, osteoporosis, coronary heart disease, painful breast tension, edema, fatigue, decreased sexual activity, as well as subsequent psychosocial problems (Payer, 1990, Rekers, 1990). additionally It is claimed that estrogens have neuroprotective effects. Decreasing estrogen concentrations can therefore the mental activities adversely affect aging women (Schneider & Finch, 1997; Wickelgren, 1997). estradiol is for that known, excellent for the treatment of climacteric symptoms to be, and its use in the treatment of these symptoms rises rapidly. estrogens however cause an increased risk of endometrial and Breast cancer. It is possible, carcinogenicity of endometrial cancer by sequential administration of progestin to lower, but the risk for Breast cancer is not reduced by progestins. The carcinogenicity risk limits the length of estrogen replacement treatment, although it is very useful that would be Treatment due to the protective Effects of estrogens in the bones, in the cardiovascular System, in the central nervous system and urinary symptoms in the long term continue.

"SERM" s (Selective Estrogen Receptor Modulators) have both estrogen-like like antiestrogenic properties (Kauffman & Bryant, 1995). The effects can, as in the case of tamoxifen and toremifene, the estrogen-like effect in the bone, partially estrogen-like Effect in the uterus and the liver and pure anti-estrogenic effect in breast cancer have to be tissue-specific. Raloxifene and droloxifen are too Tamoxifen and Toremifen similar, except that their anti-estrogens Properties dominate. Based on the published information All SERMs are more likely to cause climacteric symptoms than to prevent them. They still have other important benefits in elderly women: they lower total and lower LDL cholesterol therefore the risk of cardiovascular Illnesses and they can Prevent osteoporosis and breast cancer growth in postmenopausal Inhibiting women. There are also almost pure antiestrogens in development. she are mainly focused on the treatment of breast cancer (Wakeling & Bowler, 1988).

The Compound (desaminohydroxy) toremifene, which is also under code FC-1271a or the generic name ospemifene, has relatively weak estrogens and antiestrogenic effects in the classical hormonal tests (Kangas, 1990). It has anti-osteoporotic effects and lowers Total and LDL cholesterol levels, both in experimental models, as well as in human volunteers (International patent publications WO 96/07402 and WO 97/32574). She also has antitumor activity in one early stage breast cancer development in an animal breast cancer model. Ospemifen is the first SERM for which it was shown that it was cheap Has effects on climacteric syndromes in healthy women.

The European patent application EP 664124 A1 suggests the use of raloxifene or related compounds to inhibit skin atrophy or vaginal atrophy, especially in postmenopausal women.

WHERE 02/07718 discloses that the ospemifene, i.e., (desaminohydroxy) toremifene, is effective in treating vaginal dryness. However, taught the document is not about it, that Ospemifs are against any urinary symptoms or against others vaginal symptoms would be effective.

US 5,352,699 discloses a method of treating vaginal atrophy by topically administering retinoic acid.

US 5,747,059 notes that 1-centochroman has beneficial effects on vaginal mucosa in animal experiments. However, there are essential differences in the structures between compound (I) of the present invention and 1-centochroman: Compound (I) is a triphenylalkene (specific triphe nylbutene) compound, whereas the compounds disclosed in the cited document are triphenylalkane compounds wherein the alkane chain has formed a ring together with a hydroxy substituent in a phenyl group. In addition, the compounds disclosed in the cited reference are not considered SERMs.

US 2001034340 A1 refers to a method of treating vaginal atrophy by administering conjugated estrogens, especially conjugated equine estrogens, USP, and medroxyprogesterone acetate. SERMs are not suggested for this purpose.

SUMMARY OF THE INVENTION

oder eines geometrischen Isomers, eines Stereoisomers, eines pharmazeutisch verträglichen Salzes davon oder eines Metaboliten davon, ausgewählt aus der Gruppe, bestehend aus TORE VI (4-Hydroxy(desaminohydroxy)toremifen), TORE VII (4,4'-Dihydroxy(desaminohydroxy)toremifen, TORE XVIII ((Desaminocarboxy)toremifen), TORE VIII (4-Hydroxy(desaminocarboxy)toremifen) und TORE XIII (Toremifenmonophenol), zur Herstellung einer pharmazeutischen Zusammensetzung zur Hemmung von urogenitaler Atrophie bei Frauen, wobei sich urogenitale Atrophie bezieht auf

• i) Harnsymptome bzw. Symptome der Harnwege, ausgewählt aus der Gruppe bestehend aus Störungen der Mikturation, Dysurie, Hämaturie, Frequenz des Harnlassens, Empfindung der Dringlichkeit, Harnwegsinfektionen, Harnwegsentzündung, Nokturie, Harn-Inkontinenz, Inkontinenz bei Drang und unfreiwilligem Harnabgang oder
• ii) vaginalen Symptomen, ausgewählt aus der Gruppe bestehend aus Reizung, Jucken, Brennen, übelriechendem Ausfluss, Infektion, Leukorrhoe, Pruritus der Schamlippen, Gefühl von Druck und postkoitalem Bluten.

In one aspect, this invention relates to the use of the compound of formula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt thereof or a metabolite thereof selected from the group consisting of TORE VI (4-hydroxy (desaminohydroxy) toremifene), TORE VII (4,4'-dihydroxy (desaminohydroxy) toremifene , TORE XVIII ((desaminocarboxy) toremifene), TORE VIII (4-hydroxy (desaminocarboxy) toremifene) and TORE XIII (toremifene monophenol), for the preparation of a pharmaceutical composition for inhibiting urogenital atrophy in females, which refers to urogenital atrophy

• Urinary symptoms of the urinary tract selected from the group consisting of disorders of micturition, dysuria, hematuria, frequency of urination, urgency, urinary tract infections, urinary tract infection, nocturia, urinary incontinence, incontinence in urgency and involuntary discharge of urine or
• ii) vaginal symptoms selected from the group consisting of irritation, itching, burning sensation, malodorous discharge, infection, leucorrhea, pruritus of the labia, sensation of pressure and postcoital bleeding.

oder eines geometrischen Isomers, eines Stereoisomers, eines pharmazeutisch verträglichen Salzes davon oder eines Metaboliten davon, ausgewählt aus der Gruppe, bestehend aus TORE VI (4-Hydroxy(desaminohydroxy)toremifen), TORE VII (4,4'-Dihydroxy(desaminohydroxy)toremifen, TORE XVIII ((Desaminocarboxy)toremifen), TORE VIII (4-Hydroxy(desaminocarboxy)toremifen) und TORE XIII (Toremifenmonophenol), zur Herstellung einer pharmazeu tischen Zusammensetzung zur Behandlung oder Vorbeugung von Symptomen verbunden mit urogenitaler Atrophie bei Frauen, wobei die Symptome sind:

• i) Harnsymptome bzw. Symptome der Harnwege, ausgewählt aus der Gruppe bestehend aus Störungen der Mikturation, Dysurie, Hämaturie, Frequenz des Harnlassens, Empfindung der Dringlichkeit, Harnwegsinfektionen, Harnwegsentzündung, Nokturie, Harn-Inkontinenz, Inkontinenz bei Drang und unfreiwilligem Harnabgang oder
• ii) vaginalen Symptomen, ausgewählt aus der Gruppe bestehend aus Reizung, Jucken, Brennen, übelriechendem Ausfluss, Infektion, Leukorrhoe, Pruritus der Schamlippen, Gefühl von Druck und postkoitalem Bluten.

In another aspect, the invention relates to the use of the compound of formula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt thereof or a metabolite thereof selected from the group consisting of TORE VI (4-hydroxy (desaminohydroxy) toremifene), TORE VII (4,4'-dihydroxy (desaminohydroxy) toremifene , TORE XVIII ((desaminocarboxy) toremifene), TORE VIII (4-hydroxy (desaminocarboxy) toremifene) and TORE XIII (toremifene monophenol), for the preparation of a pharmaceutical composition for the treatment or prevention of symptoms associated with urogenital atrophy in women, with the symptoms are:

• i) urinary symptoms or urinary symptoms selected from the group consisting of disorders of micturition, dysuria, hematuria, frequency of urination, urgency, urinary tract infections, urinary tract infection, nocturia, urinary incontinence, incontinence in urgency and involuntary urination or
• ii) vaginal symptoms selected from the group consisting of irritation, itching, burning sensation, malodorous discharge, infection, leucorrhea, pruritus of the labia, sensation of pressure and postcoital bleeding.

BRIEF DESCRIPTION OF THE FIGURES

1A to 1D show changes (from start to 12 weeks of treatment) in the karyopyknose index for surface cells of the vaginal epithelium for the individuals given daily with 30 mg ospemifene, ie FC-1271a (1A), 60 mg FC-1271a (1B), 90 mg FC-1271a (1C) and 60 mg raloxifene (1D).

DETAILED DESCRIPTION OF THE INVENTION

The uses according to the invention are for Women during or especially useful after menopause. Nevertheless, the use according to the invention not limited to women in this age group.

The The invention particularly relates to the use of the estrogen receptor modulator ospemifene in women during or after menopause. Ospemifene is the Z-isomer of the compound of formula (I), and it is one of the main metabolites of Toremifen, it is known for this, an estrogen agonist and antagonist (Kangas, 1990; International Patent Applications WO 96/07402 and WO 97/32574).

Of the The term "metabolite" should be understood as such be that he mentioned the oxidation metabolites mentioned in Kangas (1990) on page 9 (TOR VI, TORE VII, TORE XVIII, TORE VIII, TORE XIII), in particular TORE VI and TORE XVIII.

The Use of mixtures of isomers of the compound (I) is also intended be included in this invention.

The Atrophy, which is to inhibit, is urogenital atrophy. With urogenital Atrophy-related symptoms can be be divided into two subgroups: urinary symptoms and vaginal symptoms.

When Examples of urinary symptoms or symptoms of the urinary tract may be disorders of the Micturition, Dysuria, Hematouria, Frequency of urination, sensation of urgency, urinary tract infections, urinary tract inflammation, Nocturia, urinary incontinence during urgency and involuntary discharge of urine to be named.

When Examples of vaginal symptoms can be Irritation, itching, burning, foul-smelling Outflow, infection, leucorrhoea, pruritus of the labia, feeling of pressure and postcoital bleeding.

The Effect of atrophy of the skin is cosmetic, but can also be with pathological conditions, like reduced ability the skin to undergo wound healing. Atrophy or Aging of the skin occurs as a change in smoothness and Texture, causing roughness in appearance and feel of the outer surface of the Skin, change the elasticity of the skin, which effects the mechanical properties of the skin and changes skin pigmentation. Skin aging in postmenopausal women may also as a decrease in mitotic rate of keratinocytes, changes in skin thickness and decrease of glucosaminoglucans and soluble Collagen, which is linked to the moisture content of the skin, be measured.

The new and surprising Effects of ospemifene were detected in a clinical study. In This study was elderly female volunteers raloxifene (60 mg / day) or ospemifene at different doses during one Duration of 3 months. At the dose levels of 30, 60 and 90 mg ospemifene Every day a significant decrease in vaginal atrophy was observed. These Properties are new and unique among the well-known selective estrogen receptor modulators (SERMs) and show that ospemifene in doses of 25 mg to something less than 100 mg daily, especially 30 to 90 mg daily, successful can be used to prevent atrophy, especially urogenital Atrophy in women during or after menopause, to relieve symptoms that have been eliminated. Furthermore has ospemifene compared to any known anti-estrogen or SERM connection a superior Profile estrogenic and antiestrogenic Effects.

The compound (I) according to the invention in various ways, such as oral, topical, transder oral, intravaginal or subcutaneous routes, of which oral or transdermal routes of administration are the most preferred.

suitable Close forms of preparation e.g. Tablets, capsules, granules, powders, suspensions, syrups and transdermal formulations, ointments, creams or gels. Also Subcutaneous implants may be for prolonged use useful be. For vaginal local release are vaginal creams, gels, vaginas, vaginal tablets, Pessaries or vaginal rings preferred.

EXPERIMENTS

A Phase I-II clinical trial was conducted to evaluate the effects of Ospemifen on endometrial thickness, endometrial pathology (biopsy taken through curettage, as described by Vuopala et al., 1982) and portio smears in healthy postmenopausal female volunteers in the age range from 55 to 69 years to study. Tolerability and pharmacokinetics were also found. Raloxifene (60 mg daily) was used as a reference. Ospemifene was given orally in doses of 30, 60 and 90 mg daily. There were 29 volunteers at each dose level, as well as in the raloxifene group. Ospemifene was dissolved in gelatin capsules containing either 30, 60 or 90 mg ospemifene. The thickness of the endometrium was through Ultrasound diagnostics evaluated using a Hitachi EUB-405 device. The vaginal epithelium was assessed by Karyopyknose Index, the is a well-known method of evaluation. In this Procedure is the vaginal portion of portio smears as a percentage Calculated the number of cells of different layers: the parabasal Cell layer, the intermediate Cell layer and the superficial Cell layer. Estrogenicity shows by a shift towards the proportion of superficial Cells. In postmenopausal women, this proportion is usually near zero, and estradiol treatment increases the proportion to near 100. Samples were taken before and after Treatment (at 3 months) taken.

Evaluation of vaginal estrogens Effect of Ospemifene (Reference Example)

table 1 shows the change in the maturity index for parabasal cells (MI 1) and in the maturity index for superficial cells (MI 3) 3-month administration of different doses of ospemifen or Raloxifene.

Table 1. Change in parabasal cell maturity index (MI 1) and superficial cell maturity index (MI 3) after 3 months administration of various doses of ospemifene or raloxifene. (MI 1: index 100 no estrogenicity, index 0 full estrogen and MI 3: index 100 full estrogen, index 0 no estrogenicity).

1A to 1D show changes (from start to 12 weeks of treatment) in the karyopyknose index for surface cells of the vaginal epithelium for the individuals given daily with 30 mg ospemifene (1A), 60 mg ospemifene (1B), 90 mg ospemifene (1C) and 60 mg Raloxifene (1D) were treated. In the figures, the code FC-1271a is used instead of the generic name Ospemifen.

Portio smear scores show that nobody in the raloxifene group ( 1D ) had a significant change in the karyopyknose index for superficial cells from baseline to treatment completion. Most of the individuals in the ospemifene group had slight increases in the index, but in the rest of the subjects the estrogenic effect was very weak, if measurable at all. In all cases, the increase was small (<40, except in one case, which was 45 in the 90 mg group) compared to estradiol, which is known to increase the index by nearly 100. A weak but statistically significant estrogenic effect in the portio smears was thus demonstrated. No pathological changes were detected in any of the samples.

Evaluation of endometrial estrogens Effect of Ospemifene (Reference Example)

ospemifene had a weak estrogen Effect on endometrial histology. This effect is clear weaker as the one in estrogen replacement therapy is detected. There were no malignant findings in the endometrium. The thickness of the endometrium, as assessed by ultrasound diagnostics, showed only a small, statistically insignificant increase in thickness (average 0.2 mm, 0.5 mm and 0.5 mm) at the dose heights of 30, 60 or 90 mg. The measured values were always smaller than 8 mm, which is considered to be a thickness sufficient for a physiologically significant estrogenicity of SERMs, as tamoxifen, is indicative (Hann et al., 1997; Lahti et al., 1993).

Effect on urogenital Atrophy and related symptoms

In The clinical Phase I and II studies are 241 postmenopausal Women have been treated with Ospemifen. 77 were taken with 25-30 mg, 78 with 50-60 mg, 78 with 90-100 mg and 8 with 200 mg daily Dose ospemifene treated. In the control groups were 47 with Placebo and 29 treated with raloxifene. Some of the subjects reported spontaneously over Relief of symptoms associated with urogenital atrophy. The symptoms shut down both vaginal and urinary symptoms, such as vaginal discomfort with irritation, itching, burning sensation, pain, postcoital bleeding, itching labia minora and / or malodorous Vaginal discharge and leucorrhoea. The mitigated in individual cases Close urinary symptoms Urinary incontinence, recurrent urinary tract infections, disorders of micturition, frequency of urination, nocturia, sensation of urgency, incontinence in case of urgency and involuntary discharge of urine. The hospital doctors also reported Cases, where signs of urogenital atrophy, such as vaginal pallor, petechiae, Friability, atrophy of the vaginal mucosa and ulceration due to Ospemifen were alleviated.

On the basis of the present Data is expected to be the optimal clinical dose higher than 25 mg daily and lower than 100 mg daily is. A particularly preferable daily dose will be in the range found from 30 to 90 mg. At the higher doses (100 and 200 mg Every day) shows ospemifene properties similar to those of tamoxifen and toremifene are. Ospemifen is a particularly valuable drug because of it an excellent compatibility has. additionally Ospemifen reduces total and LDL cholesterol, increases HDL cholesterol and prevented Osteoporosis and early breast cancer. The present invention indicates that ospemifene and Other compounds of formula (I) also currency end menopause as hormone replacement therapy instead of estrogens, which is known to increase the risk of breast and endometrial cancer boost, can be used.

It is estimated be that the methods of the present invention in the design a selection of embodiments flow in can, of which only a few are revealed here. It will be for the expert be obvious that other embodiments exist and do not deviate from the spirit of the invention. Therefore, the described embodiments by way of example and not to be construed as limiting.

LITERATURE REFERENCES

• Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337: 1641-1647, 1997
• Ettinger B, Genant HK, Cann CE: Long-term estrogen replacement Therapy prevents bone loss and fractures. Ann Intern Med 102: 319-324, 1985
• Hann LE, Giess CS, Bach AM, Tao Y, Tree HJ, Barakat RR: Endometrial thickness in tamoxifen-treated patients: correlation with clinical and pathologic findings. Am J Roentgenol 168: 657-661, 1997
• Gustafsson J-A: Estrogen receptor β-getting in on the action? Nature Medicine 3: 493-494, 1997
• Kangas L: Biochemical and pharmacological effects of toremifene metabolites. Cancer Chemother Pharmacol 27: 8-12, 1990 Kauffman RF, Bryant HU: Selective Strogen receptor modulators. Drug News Perspect 8: 531-539, 1995
• Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen M, Taskinen PJ, Laatikainen T: Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 81: 660-664, 1993
• Palkowitz AD, Glasebrook AL, Thraser KJ, Hauser KL, Short LL, Phillips DL, Muchi BS, Sato M, Shetler PK, Cullinan GJ, Pell TR, Bryant HU: Discovery and synthesis of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene: a novel, highly potent, selective estrogen receptor modulator. Med Chem 40: 1407-1416, 1997
• Payer L: The menopause in various cultures. In: A portrait of the menopause. Expert reports on medical and therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, NJ, USA, 1991. pp. 3-22
• Rekers H: Matering the menoause. In: A portrait of the menopause. Expert reports on medical and therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, NJ, USA, 1991. pp. 23-43
• Schneider LS, Finch CE: Can estrogens prevent neurodegeneration. Drugs & Aging 11: 87-95, 1997
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Claims (5)

Use of a compound of the formula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt thereof or a metabolite thereof selected from the group consisting of TORE VI (4-hydroxy (desaminohydroxy) toremifene), TORE VII (4,4'-dihydroxy (desaminohydroxy) toremifene ), TORE XVIII ((desaminocarboxy) toremifene), TORE VIII (4-hydroxy (desaminocarboxy) toremifene) and TORE XIII (toremifene monophenol), for the preparation of a pharmaceutical composition for inhibiting urogenital atrophy in females, where urogenital atrophy refers to i) Urinary symptoms selected from the group consisting of disorders of micturition, dysuria, hematuria, frequency of urination, urgency, urinary tract infections, urinary tract inflammation, nocturia, urinary incontinence, urinary incontinence and involuntary leakage, or ii) vaginal symptoms selected from the group from irritation, itching, burning sensation, foul odor, infection, leucorrhea, pruritus of pubic ips, feeling of pressure and postcoital bleeding. Use according to claim 1, wherein the compound (I) Ospemifene is. Use of the compound of the formula (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt thereof or a metabolite thereof selected from the group consisting of TORE VI (4-hydroxy (desaminohydroxy) toremifene), TORE VII (4,4'-dihydroxy (desaminohydroxy) toremifene ), TORE XVIII ((desaminocarboxy) toremifene), TORE VIII (4-hydroxy (desaminocarboxy) toremifene) and TORE XIII (toremifene monophenol), for the preparation of a pharmaceutical composition for the treatment or prevention of symptoms associated with urogenital atrophy in women, with the symptoms are: i) urinary symptoms selected from the group consisting of disorders of micturition, dysuria, hematuria, frequency of urination, urgency, urinary tract infections, urinary tract infection, nocturia, urinary incontinence, urinary incontinence and involuntary urinary leakage, or ii) vaginal symptoms from the group consisting of irritation, itching, burning, foul-smelling discharge, infection, leucorrhea hoe, pruritus of the labia, feeling of pressure and postcoital bleeding. Use according to claim 3, wherein the compound (I) Ospemifene is. Use according to one of the preceding claims, wherein the compound is oral, topical, transdermal, intravaginal or subcutaneous is administered.